Search

Starting from 5-methylhexanal and (S)-configured N-propargylprolinol ethers, coupling delivered N-(4-hydroxynon-2-ynyl)prolinol derivatives as mixtures of C4 diastereomers. Resolution of the epimers succeeded after introduction of an (R)-mandelic ester derivative and subsequent HPLC separation. Alternatively, suitable oxidation gave the corresponding alkynyl ketone. Midland reagent controlled diastereoselective reduction afforded a defined configured propargyl alcohol with high selectivity. LiAlH4 reduction and Mosher analyses of the allyl alcohols enabled structure elucidation. The suitably protected products are used as key intermediates in enantioselective Streptomyces γ-butyrolactone signaling molecule total syntheses.

The enantioselective Michael addition of isobutyraldehyde to nitroolefin analogs was achieved by utilizing an α,α-diphenyl-(S)-prolinol-derived chiral diamine catalyst 1b. In this protocol, catalys...

Spectroscopic characterizations of key reaction intermediates are often considered the final confirmation of a reaction mechanism. This proof‐of‐principle study showcases the application of vibrational circular dichroism (VCD) spectroscopy for the characterization of in situ generated reaction intermediates using the key intermediates of enamine catalysis of Jørgensen–Hayashi‐type prolinol ether catalysts as model system. By comparison of experimental and computed spectra, the enamines are shown to preferentially adopt an anti‐conformation with E‐configured C=C bond. For the parent prolinol catalyst, the structure and stereochemistry of the oxazolidine side product is determined as well. This study thus demonstrates that VCD spectra can provide insights into structural preferences of organocatalysts that utilize a covalent activation mechanism. Thereby it outlines new fields of applications for VCD spectroscopy and finally adds the technique to the toolbox of physical organic chemistry for in‐depth mechanistic studies., Before it reacts: The enamine and oxazolidine intermediates are characterized by in situ IR and VCD spectroscopy. The study demonstrates the proof‐of‐principle for such analysis of asymmetric catalysts employing a covalent substrate activation mechanism by VCD spectroscopy.Stereochemistry of the reaction intermediates of prolinol ether catalyzed reactions characterized by vibrational circular dichroism spectroscopy (Merten and Golub @MertenLab @ruhrunibochum)

Summary p-Methyl benzaldehyde (p-MBA) is a class of key chemical intermediates of pharmaceuticals. Conventional industrial processes for p-MBA production involve the consecutive photochlorination, amination, and acid hydrolysis of petroleum-derived p-xylene, while producing vast pollutants and waste water. Herein, we report a direct, green route for selective synthesis of p-MBA from acetaldehyde using a diphenyl prolinol trimethylsilyl ether catalyst. The optimized p-MBA selectivity is up to 90% at an acetaldehyde conversion as high as 99.8%. Intermediate structure and 18O-isotope data revealed that the conversion of acetaldehyde to p-methylcyclohexadienal intermediates proceeds in an enamine-iminium intermediate mechanism. Then, controlled experiments and D-isotope results indicated that the dehydrogenation of p-methylcyclohexadienal to p-MBA and H2 is catalyzed by the same amines through an iminium intermediate. This is an example that metal-free amines catalyze the dehydrogenation (releasing H2), rather than using metals or stoichiometric oxidants., Graphical abstract, Highlights • A direct route to produce p-methyl benzaldehyde from biomass-derived acetaldehyde • Revealing the reaction kinetics and mechanism under reaction conditions • An example of an organic amine-catalyzed dehydrogenation-aromatization reaction

A density functional study of the [2 + 2] cycloaddition between methyleneindolinones and enals catalyzed by prolinol derivatives is presented here. The calculations show that dienamines could be generated under acid-free conditions, and the hydroxyl of the catalysts plays a key role in the formation of dienamines. The following cycloaddition process between methyleneindolinones and the new formed dienamines includes two-step intramolecular electron transfers. The stereoselectivity is mainly attributed to the charge distributions on the reaction centers and the H-bonding interaction between the catalysts and methyleneindolinones. The excellent 3,4-regioselectivity is largely ascribed to the fact that the pre-product of 1,2-reactivity is tough to hydrolyze, but could return to the precursor. Besides, the large steric hindrance of catalysts is not conducive to the 3,4-reactivity, while the H-bonding between the catalysts and methyleneindolinones has less effect on the regioselectivity.

α,α-L-Diaryl prolinol was first introduced into a highly stable porous MOF, UiO-67, via the immobilization of a chiral prolinol side chain into 4,4′-biphenyldicarboxylic acid through a five-step process, to construct a chiral heterogeneous catalyst. The catalyst exhibited high yield (up to 88%) and excellent stereoselectivities (up to >4:1 dr, > 80% ee) for the enantioselective hydration/aldol/oxa-Diels Alder domino reactions, as well as good reusability with recycle use for three times without significant loss of activity. To our knowledge, this is the first report of chiral MOFs as heterogeneous catalysts for asymmetric domino reactions.

Despite intense interest in amine-catalyzed stereoselective reactions, high catalyst loadings of ≥10 mol % are still common and either due to low reactivity or catalyst deactivation. Yet, few deactivation pathways are well understood. Here, we unraveled the deactivation of secondary amines by undesired aldol reaction. Mechanistic studies with peptide and prolinol silyl ether catalysts showed the generality of this so-far underappreciated catalyst deactivation pathway. The insights enabled conjugate addition reactions between aldehydes and nitroolefins on a multigram scale in the absence of solvent—conditions that are attractive as environmentally benign processes—with excellent product yields and stereoselectivities in the presence of as little as 0.1 mol % of a chemoselective peptidic catalyst. © American Chemical Society 2020 ISSN:0022-3263 ISSN:1520-6904

Azanucleosides, the sugar-modified nucleoside analogues, have various biological activities, while their efficient synthetic strategy is still under development. Herein, a novel method for the synthesis of pharmaceutically relevant azanucleosides, β-anomers of ribo-azanucleosides, by means of site-specific anodic C-H activation by using a nitroalkane-lithium perchlorate medium is reported. A mechanistic study of the electrochemical reaction and the armed/disarmed concept from traditional glycochemistry revealed that the 2'-substituent has a significant effect on the reactivity of prolinol derivative, and suitable carboxylic acid additives can control the reactivity of the intermediate species, an iminium cation equivalent. Finally, this method was demonstrated to be applicable for the synthesis of β-anomers of ribo-azanucleosides with all four nucleobases in a stereoselective manner.

The first highly diastereo- and enantioselective synthesis of bridged O, O-acetals embedded with spirooxindoles has been developed. Dioxindoles and 2-hydroxy cinnamaldehydes were employed as the reaction partners in this method. The desired products were obtained via diaryl prolinol TBS ether catalyzed Michael reaction followed by acetal formation with TFA.

An efficient enantioselective total synthesis of pyrrolo-[2,1-c][1,4]benzodiazepine (PBD) monomers (S)-(−)-barmumycin and (S)-(+)-boseongazepine B and collective formal total syntheses of oxoprothracarcin, prothracarcin and (S)-(+)-boseongazepine C are described. The present approach is based on an efficient construction of an ethylidene substituted C-4 pyrrolidine core, that is the stereocontrolled introduction of a trisubstituted double bond through simple enolate α-alkylation of an ester, which also relies on a proline catalysed asymmetric α-amination followed by HWE olefination. The present synthetic route possesses superior stereocontrol over the C-4 ethylidene substituent as well as the C-(S) stereogenic center, which allows more functional variations on the five-membered prolinol core as compared to the existing PBD synthesis.

A 1,1'-bi-2-naphthol (BINOL)-aldehyde-based polymer has been synthesized that exhibits enantioselective fluorescent enhancement toward prolinol. It is found that the polymer shows greatly amplified enantioselectivity over the parent small-molecule sensor under the same conditions. This is attributed to the photoinduced electron transfer processes between the BINOL units in the polymer chain as well as the different steric environment provided by the polymer.

A novel category of di(N,N-dimethylbenzylamine)prolinol silyl ether catalyst, which when used in conjunction with an acidic co-catalyst, generates an ammonium salt supported organocatalyst. This catalytic system is shown to be very effective for the Michael reaction of benzyloxyacetaldehyde and various nitroolefins in isopropanol. Excellent enantioselectivities (up to 99%) and diastereoselectivities (syn/anti of 75:25) and short reaction times were obtained. The presence of the bulky OTMS group combined with the presence of two large N,N-dimethylbenzyl ammonium ion groups accounts for the effectiveness of this catalytic system.

Total synthesis of the proposed structure of baulamycin A was performed. The spectral properties of the synthetic compound differ from those reported for the natural product. On the basis of comprehensive NMR study, we proposed two other possible structures for natural baulamycin A. Total syntheses of these two substances were performed, which enabled assignment of the correct structure of baulamycin A. Key features of the convergent and fully stereocontrolled route include Evans Aldol and Brown allylation reactions to construct the left fragment, a prolinol amide-derived alkylation/desymmetrization to install the methyl-substituted centers in the right fragment, and finally, a Carreira alkynylation to join both fragments. In addition, we have determined the inhibitory activities of novel baulamycin A derivatives against the enzyme SbnE. This SAR study provides useful insight into the design of novel SbnE inhibitors that overcome the drug resistance of pathogens, which cause life-threatening infections.

Prolinol-phosphine chiral ligands enabled highly enantioselective copper-catalyzed intermolecular alkyne-nitrone coupling (Kinugasa reaction) to produce 1,3,4-trisubstituted chiral β-lactams. A high level of enantiocontrol was achieved not only with aryl- or alkenylacetylenes but also with alkylacetylenes, which were important but unfavorable substrates in the previously reported protocols. Two-point hydrogen bonding between the chiral ligand and the nitrone oxyanion consisting of O-H⋅⋅⋅O and C(sp3 )-H⋅⋅⋅O hydrogen bonds is proposed.

The Brønsted acid-catalyzed intramolecular hydroalkoxylation and hydroamination of unactivated alkynes are described. We found that unactivated alkynes are electrophilically activated by a catalytic amount of bis(trifluoromethanesulfonyl)imide to undergo intramolecular hydroalkoxylation and hydroamination. In the presence of silane, the formed reactive exo-cyclic enol ether and exo-cyclic enamine intermediates are effectively reduced to the corresponding saturated cyclic ethers and N-protected cyclic amines. The 2,4-cis and 2,5-cis pyrrolidine derivatives are produced with high diastereoselectivity. Taking advantage of this selectivity, the 2,5-cis-disubstituted prolinol was also synthesized from glutamic acid in the optically active form.

The first acid-promoted reaction system to form azaheterocycles from N-carbamate-protected amino alcohols is described. The reaction involves the activation of the hydroxyl group via the use of orthoesters. Despite the reduced nucleophilicity of carbamate nitrogen, this reaction system provides several types of pyrrolidines and piperidines in good to high yields. Using this protocol, prolinol derivatives can also be synthesized from carbamate-protected amino diols with regio- and stereoselectivity.

N-Alkylation of 2-azidobenzenesulfonamide with 5-bromopent-1-ene gave an N-pentenyl sulfonamide, which underwent intramolecular aminohydroxylation to give an N-(2-azidoaryl)sulfonyl prolinol, a precursor for the synthesis of a pyrrolobenzothiadiazepine. The attempted N-alkylation of 2-azidobenzamide gave a separable mixture (∼1:1) of a benzotriazinone and a quinazolinone in a 72% combined yield. Other primary alkyl halides (3 examples) gave similar mixtures of benzotriazinones and quinazolinones. Benzylic, allylic, and secondary and tertiary alkyl halides (5 examples) gave only benzotriazinones in moderate yields. The results of mechanistic studies show the likely involvement of nitrene intermediates in the quinazolinone pathway and a second pathway involving a dimethylsulfoxide or dimethylsulfide-mediated conversion of 2-azidobenzamide into benzotriazinones.

A metal-free oxyamination reaction of alkenes with ambient CO2 is reported. In the presence of I2 and DBU, CO2 is applied in situ as a protecting group to regulate the nucleophilicity of the amino group and facilitate the bicyclization of 4-pentenamines with high chemoselectivity. Moreover, this reaction provided a feasible approach to prepare prolinol carbamates with good tolerance of functional groups and high efficiency under mild conditions.

A novel approach for the asymmetric synthesis of (6 R )-4-hydroxy-6-substituted-δ-lactones has been achieved using asymmetric reduction of a prochiral ketone in the presence of ( S )-(−)-diphenyl-prolinol/borane as a key step. The enantiomeric purity of the products was determined by chiral GC.

The total synthesis of dolastatin 16, a macrocyclic depsipeptide first isolated from the sea hare Dolabella auricularia as a potential antineoplastic metabolite by Pettit et al., was achieved in a convergent manner. Dolastatin 16 was reported by Tan to exhibit strong antifouling activity, and thus shows promise for inhibiting the attachment of marine benthic organisms such as Amphibalanus amphitrite to ships and submerged artificial structures. Therefore, dolastatin 16 is a potential compound for a new, environmentally friendly antifouling material to replace banned tributyltin-based antifouling paints. The synthesis of dolastatin 16 involved the use of prolinol to prevent formation of a diketopiperazine composed of l-proline and N-methyl-d-valine during peptide coupling. This strategy for the elongation of peptide chains allowed the efficient and scalable synthesis of one segment, which was subsequently coupled with a second segment and cyclized to form the macrocyclic framework of dolastatin 16. The synthetic dolastatin 16 exhibited potent antifouling activity similar to that of natural dolastatin 16 toward cypris larvae of Amphibalanus amphitrite.

A new analogue of the proline derived organocatalyst ‘pyrrolidine-HOBt’ has been designed and synthesized from l -prolinol and hydroxybenzotriazole (HOBt) employing a simple reaction protocol. The catalyst was found to be effective in promoting the asymmetric Michael addition of cyclohexanone to nitroolefins using water as the reaction medium. The reaction products γ-nitrocarbonyls are obtained in good yields and stereoselectivities.

A series of 3-nitrophenyl and 3-hydroxyphenyl ethers of (S)-N-methylprolinol bearing bulky and lipophilic substituents at phenyl C5 were tested for affinity at α4β2 and α3β4 nAChRs. The two phenyl ethers 5-substituted with 6-hydroxy-1-hexynyl showed high α4β2 affinity and significantly increased α4β2/α3β4 selectivity compared to the respective unsubstituted parent compounds. Within the two series of novel phenyl ethers, we observed parallel shifts in affinity and, furthermore, the increase in α4β2/α3β4 selectivity resulting from the hydroxyalkynyl substitution parallels that reported for the same modification at the 3-pyridyl ether of (S)-N-methylprolinol (A-84543), a well-known potent α4β2 agonist. On the basis of these results, our nitrophenyl and hydroxyphenyl prolinol ethers can be considered bioisosteres of the pyridyl ether A-84543 and lead compounds candidable to analogous optimization processes.

Using (S)-prolinol as a chiral auxiliary, axially chiral vinylallenes with excellent enantiopurity (up to >99% enantiomeric excess (ee)) were readily prepared from optically pure propargylamines in...

A copper/prolinol-phosphine chiral catalyst enabled the one-step synthesis of chiral α-alkylidene-β-lactams. Optimization of the chiral ligand for steric and electronic properties realized the highly enantioselective coupling of nitrones and propargyl alcohol derived alkynes. The resulting chiral α-alkylidene-β-lactams served as a platform for various β-lactams via well-established transformations of α,β-unsaturated carbonyl compounds.

Aqueous interactions of a novel ester-bonded Gemini prolinol-based surfactant, 2,2′-((adipoylbis(oxy))bis(methylene))bis(1-dodecyl-1-methylpyrrolidin-1-ium) bromide C12-6-C12PB, with dodecyl sodium sulfate (SDS), dodecyl trimethyl ammonium bromide (DTAB), tetradecyl trimethyl ammonium bromide (TTAB), or cetyltrimethyl ammonium bromide (CTAB) were studied using conductomeric measurement. The experimental critical micelle concentration (CMC) was lower than the ideal CMC, and the negative interaction parameters indicate that there is a synergistic interaction between the surfactants in the binary solution. The solubilization capacities of single and binary surfactant systems towards polycyclic aromatic hydrocarbons (PAHs) (i.e., naphthalene, anthracene, and pyrene) were evaluated and are discussed in terms of the molar solubilization ratio (MSR), micelle-water partition coefficient (Km), and free energy of solubilization (ΔGso). C12-6-C12PB and SDS respectively had the minimum and maximum MSR when presented individually in the solution. The MSR values in the binary system are greater than those in the single surfactant system, and this indicates that synergism in a mixed system enhances PAH solubility. With a molar ratio of 0.7:0.3, C12-6-C12PB/SDS had a relatively greater solubilization capacity for PAHs because of large aggregates. The negative value of ΔGso indicates the spontaneity of the solubilization process.

A catalytic highly enantioselective aza-Reformatsky reaction with cyclic aldimines and ketimines for the synthesis of chiral b-amino esters with good yields and excellent enantioselectivities is reported.Areadily available diaryl prolinol is used as a chiral ligand, ZnMe2 as a zinc source and ethyl iodoacetate as reagent in the presence of air atmosphere. The reaction with cyclic ketimines generates a quaternary stereocenter with excellent levels of enantioselectivity. Furthermore, five-membered N-sulfonyl ketimines were used as electrophiles with good enantiomeric excesses, under the optimized reaction conditions. Moreover, several chemical transformations were performed with the chiral b-amino esters., Financial support from the MINECO (Gobierno de Espana; CTQ2013-47494-P). L.D.M. thanks the Generalitat Valenciana for a predoctoral grant. C.V. thanks MINECO for a JdC contract. Access to NMR, MS and X-ray facilities from the Servei central de suport a la investigacio experimental (SCSIE)-UV is also acknowledged.

A simple, efficient catalytic asymmetric Michael addition of malonates to unsaturated ketones has been successfully developed. This process was promoted by rare earth metal complexes 1–4 bearing a chiral phenoxy functionalized prolinol ligand at room temperature [L1RE(L1H) (H2L1 = (S)-2,4-di-tert-butyl-6-((2-(hydroxydiphenylmethyl)pyrrolidin-1-yl)methyl)phenol, RE = Yb 1, Y 2, Sc 3 and L2Sc(L2H) 4 (H2L2 = (S)-2,4-di-dimethylbenzyl-6-((2-(hydroxydiphenylmethyl)-pyrrolidin-1-yl)methyl)phenol)]. Complex 3 was the best catalyst in the transformation and the products were obtained in up to 99% yield and with 90% ee. In addition, the molecular structures of the catalysts were well characterized, including X-ray determination of complex 3.

This paper describes improved reaction conditions for the substitution of the hydroxyl group in (S)-diphenyl(pyrrolidin-2-yl)methanol by the azide group, which was then reduced to the diamine derivative. We examined two protecting groups (N-Bn and N-Boc) on the pyrrolidine nitrogen in order to functionalize the primary amino group into various amide, alkylated amine, sulfonamide, thiourea and triazole derivatives. Notably, carefully controlled conditions were required to generate the desired derivatives from the sterically hindered benzhydrylamine moiety. Unexpectedly, upon removal of the N-protecting group in derivatives containing electrophilic polar double bonds (C S, C O) cyclization took place, affording products such as amidines. The target compounds were evaluated as bifunctional organocatalysts in the asymmetric Michael and Mannich addition reactions. (S)-2-(Azidodiphenylmethyl)pyrrolidine (S)-7 was identified as the most efficient organocatalyst among the various diamine derivatives of α,α-diphenyl-(S)-prolinol prepared in this work.

Synthesis of trans-4-hydroxy- d -proline and the corresponding prolinol has been accomplished starting from 4,6-di-O-benzyl-3-deoxy- d -glucal, an enol-ether derived from d -glucose, through oxidative cleavage of a vicinal diol intermediate as the key step. This work represents a practical approach to an unnatural, yet synthetically and biologically very significant, amino acid.

An organocatalytic asymmetric cascade Michael/hemiketalization/acyl transfer reaction between o-hydroxycinnamaldehydes and α-nitroketones is developed. Prolinol TMS ether catalyst in combination with benzoic acid was found to be the most effective for this reaction which proceeds through an equilibrium of lactols to provide a single diastereomer of enantiopure 2,4-disubstituted chromans.

In the context of a programme directed at the manufacture of telaprevir, eight possible approaches to its bicyclic α-amino acid core, based on organocatalytic enantioselective conjugate additions to cyclopent-1-enecarbaldehyde, were identified and preliminarily explored. Four reactions, delivering advanced intermediates en route to the target amino acid, were selected for a thorough optimisation. Three of this reactions involved iminium ion catalysis with a prolinol catalyst (addition of nitromethane, nitroacetate and acetamidomalonate) and one was based on a Cinchona-derived phase-transfer catalyst (addition of glycine imines). A careful choice of additives allowed lowering of the catalyst loading to 0.5 mol% in some cases. The preparation of intermediates that would give access to the core of telaprevir in good yields and enantioselectivities by exploiting readily available substrates and catalysts, highlights the potential of organocatalytic technology for a cost-effective preparation of pharmaceuticals.

A highly diastereoselective Grignard addition to N-tosyl- l -prolinal has been developed to deliver a variety of proline-derived vicinal amino alcohols in good to excellent yields with high diastereoselectivities. A similar selectivity was also obtained by using N-tosyl- d -prolinal. The methodology has been applied to the synthesis of medicinally important 3-hydroxy-2-phenylpiperidines.

From tentative beginnings, chiral ionic liquids have emerged into functionalized and tailor-made materials that provide novel input in classical asymmetric synthesis and separations. However, despite this broad application range the prediction of any chiral ionic liquids’ performance is difficult. We present a systematic study toward the chiral recognition properties of novel ionic liquids with an amino alcohol sub-structure derived from the chiral pool precursors ephedrine, prolinol, and phenylalaninol. The influence of different ionic head groups and core structures on the diastereomeric interactions between racemic Mosher’s acid carboxylate and enantiopure chiral ionic liquids was systematically investigated to provide insight into their recognition properties prior to application of these chiral ionic liquids in various fields.

The diastereoselective Mannich reaction of functionalized aldehydes, using a phenethylamine-derived iminium precursor, by activation with prolines and prolinol derivatives have been studied. Optimized reaction conditions have been developed, allowing for scale-up and preparation of γ-amino alcohol derivatives on multi-gram scale from β-hydroxypropanal and -butanal, with diastereoselectivites of typically >73:27 and yields of >60 %. After chromatographic diastereoisomer separation, hydrogenolytic debenzylation, enantiomerically pure Fmoc-β2-Ser(tBu)-OH and Fmoc-β2-Thr(tBu)-OH were thus prepared on multi-gram scale in 6 steps and with overall yields of 24 % and 10 %, respectively, starting from commercially available starting compounds.

Reactions of l-prolinol with aryl glyoxals lead to labile bicyclic 2-aryloyl-1,3-oxazolidines, which smoothly undergo isomerization in the presence of an acid via a cascade of reactions involving a 1,2-aryl shift. The products formed thereby were identified as bicyclic derivatives of morpholin-2-one. Both 1,3-oxazolidines and morpholin-2-ones were used for the nucleophilic trifluoromethylation by treatment with trifluoromethyltrimethylsilane (Ruppert–Prakash reagent) in the presence of a catalytic amount of CsF. Whereas in the case of the 1,3-oxazolidines only modest diastereoselectivity was achieved, the reactions with the morpholinone derivatives occurred with complete stereoselectivity.

The synthesis of α,α-diphenyl-4-trans-hydroxy-(L)-prolinol modified with imidazolium based ionic liquids was carried out with trans-α,α-diphenyl-4-hydroxy-(L)-prolinol, 5-bromovaleric acid or 1,5-dibromopentane and imidazole. α,α-Diphenyl-4-hydroxy-(L)-prolinol modified with imidazolium ionic liquid was treated with BH3·SMe2 which generate 1,3,2-oxazaborolidine, that acts as a catalyst for asymmetric reduction of prochiral ketones. α,α-Diphenyl-4-hydroxy-(L)-prolinol modified with imidazolium ionic liquids (PF6 anion) with BH3·SMe2 found to be an efficient catalyst (10 mol%) for the reduction of the acetophenone, gave 99% yield and 87–84% ee. The catalytic method has wide applicability for a variety of substrates. 1,3,2-oxazaborolidine containing ether linkage ionic liquid was recovered and reused up to 4 cycles with 99–91% yields and 87–81% ee’s.

A simple and efficient protocol for the synthesis of β-nitrostyrenes has been achieved by the use of sulfated zirconia–secondary amine (piperidine, pyrrolidine, proline or prolinol) cooperative systems. The condensation of different aldehydes and nitromethane demonstrates the efficiency of this process, which does not require high-temperature reactivation for the reuse of the catalytic material.

Background: Chiral peroxides, many of which are biologically active, are an attractive target in organic synthesis. Organocatalysts have been used for some time in the asymmetric epoxidation of α,β- unsaturated carbonyls. More recently, cinchona-derived organocatalysts have been adapted to effect the asymmetric peroxidation of unsaturated ketones. We successfully applied this catalyst system to the stereoselective peroxidation of more challenging α,β-unsaturated aldehydes with moderate enantioselectivity observed. Herein we describe our efforts to improve upon the overall stereoselectivity using prolinol-derived organocatalysts. Objective: To determine whether diarylprolinol silyl ethers are effective catalysts in the asymmetric peroxidation of α,β-unsaturated aldehydes. Methods: Using trans-2-butenal as the test substrate, peroxidation with tert-butyl hydroperoxide was attempted in a range of different solvents. The resulting β-peroxyaldehydes were oxidised in situ to afford stable β-peroxyesters. The reaction was further optimised by varying the co-catalyst and by changing the silyl ether group on the prolinol catalyst. A number of short-chain substrates were subjected to peroxidation under optimised conditions. Results: Diarylprolinol ethers were found to be effective catalysts for the enantioselective peroxidation of unsaturated aldehydes. The degree of enantioselectivity was influenced both by the choice of solvent and acid cocatalyst. Furthermore, a clear trend emerged where the level of enantioselectivity increased with increasing steric bulk of the silyl group. Conclusion: Diarylprolinol ethers are effective catalysts for the asymmetric peroxidation of α,β-unsaturated aldehydes. Under optimised conditions, short-chain substrates may be converted to the corresponding β- peroxyesters in good yields and excellent enantioselectivities.

A comprehensive survey of pathways leading to the generation of α-trifluoromethyl monocyclic piperidinic derivatives is provided (65 references). These compounds have been synthesized either from 6-membered rings e.g., pipecolic acid or lactam derivatives by introduction a trifluoromethyl group, from pyridine or pyridinone derivatives by reduction, and from 5-membered rings e.g., prolinol derivatives by ring expansion, from linear amines by cyclization or from dienes/dienophiles by [4 + 2]-cycloaddition.

A catalytic enantioselective aza-Reformatsky reaction is reported with cyclic dibenzo[b,f][1,4]oxazepines and ethyl iodoacetate leading to the synthesis of chiral ethyl 2-(10,11-dihydrodibenzo[b,f][1,4]oxazepin-11-yl)acetate derivatives with excellent yields and high enantioselectivities (up to 98% yield and 97 : 3 er) using a readily available diaryl prolinol L4 as the chiral ligand and Me2Zn as the zinc source under an air atmosphere. Furthermore, different transformations were carried out with the corresponding chiral β-amino esters, preserving in all cases the optical purity.

An easily accessible prolinol derived ligand, (S)-bis(3,5-bis(trifluoromethyl)phenyl)(pyrrolidin-2-yl)methanol, has been efficiently applied in the catalytic enantioselective addition of terminal alkynes to cyclic imines using dimethylzinc (Me2Zn) under mild reaction conditions. The developed catalytic system led to chiral propargylic sulfamidates with high yields (up to 97%) and excellent enantioselectivities (up to 97% ee).

Binding RNA targets, such as microRNAs, with high fidelity is challenging, particularly when the nucleobases to be bound are located at the terminus of the duplex between probe and target. Recently, a peptidyl chain terminating in a quinolone, called ogOA, was shown to act as a cap that enhances affinity and fidelity for RNAs, stabilizing duplexes with Watson-Crick pairing at their termini. Here we report the three-dimensional structure of an intramolecular complex between a DNA strand featuring the ogOA cap and an RNA segment, solved by NMR and restrained torsion angle molecular dynamics. The quinolone stacks on the terminal base pair of the hybrid duplex, positioned by the peptidyl chain, whose prolinol residue induces a sharp bend between the 5' terminus of the DNA chain and the glycine linked to the oxolinic acid residue. The structure explains why canonical base pairing is favored over hard-to-suppress mismatched base combinations, such as T:G and A:A, and helps to design improved high-fidelity probes for RNA.

Ring-closing olefin metathesis reactions (RCM) using Grubbs II or Hoveyda's catalysts have been applied to a series of N-alkenyl-N-benzyl-α-fluoroacrylamides. α-Fluoro-α,β-unsaturated γ- or δ-lactams incorporating a fluorinated double bond were obtained in moderate to good yields, depending on the nature of substituents on the benzyl ring. The corresponding seven- and eight-membered lactams were not formed under similar conditions. When the N-benzyl group was replaced by an N-tosyl group, the corresponding ϵ-lactam was also formed in 38 % yield. When N-(2-fluoroallyl) derivatives were used instead of fluoroacryloyl derivatives, six-, seven-, and eight-membered N-heterocycles were obtained in low yields. This method was also used to synthesize fluorinated α,β-unsaturated analogues of pyrrolizidine and indolizidine alkaloids from prolinol, and also to synthesize N-benzyl-3-fluoroquinolone in three steps from commercially available 2-vinylaniline in 44 % overall yield. Also 3-fluorocoumarin and 3-fluorochromene were prepared from o-vinylphenol, and 3-fluoro-benzoxepine was available from o-allylphenol.

A dienamine-mediated enantioselective 1,3-dipolar cycloaddition catalyzed by a chiral prolinol silyl ether catalyst has been developed. Removal of the benzamide group of the intermediates could furnish chiral C-1 substituted tetrahydroisoquinolines (see scheme) in high yields and excellent stereoselectivities.

The reaction allows the formation of xanthenones and chromans with three contiguous stereocenters with high to excellent enantioselectivity and moderate to mostly excellent diastereoselectivity.